Artificial intelligence streamlines scientific discovery of drug-target interactions.

Drug discovery is a complicated process through which new therapeutics are identified to prevent and treat specific diseases. Identification of drug-target interactions (DTIs) stands as a pivotal aspect within the realm of drug discovery and development. The traditional process of drug discovery, especially identification of DTIs, is marked by its high costs of experimental assays and low success rates.

A network-based systems genetics framework identifies pathobiology and drug repurposing in Parkinson's disease.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder. However, current treatments only manage symptoms and lack the ability to slow or prevent disease progression. We utilized a systems genetics approach to identify potential risk genes and repurposable drugs for PD.

Differences and contributors to global cognitive performance in the underrepresented Latinx Parkinson's disease population.

Despite significant progress in understanding the factors influencing cognitive function in Parkinson's disease (PD), there is a notable gap in data representation for the Latinx population. This study aims to evaluate the contributors to and disparities in cognitive performance among Latinx patients with PD. A retrospective analysis was conducted based on cross-sectional data encompassing demographic, environmental, motor, and non-motor disease characteristics from the Latin American Research Consortium on the Genetics of PD (LARGE-PD) and the Parkinson's Progression Markers Initiative (PPMI) cohorts.

Functional variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are associated with increased risk of colorectal cancer.

Background: Individuals with cystic fibrosis (CF; a recessive disorder) have an increased risk of colorectal cancer (CRC). Evidence suggests individuals with a single CFTR variant may also have increased CRC risk.

Methods: Using population-based studies (GECCO, CORECT, CCFR, and ARIC; 53 785 CRC cases and 58 010 controls), we tested for an association between the most common CFTR variant (Phe508del) and CRC risk.

Single-cell transcriptomics in a child with coenzyme Q10 nephropathy: potential of single-cell RNA sequencing in pediatric kidney disease.

Background: Coenzyme Q10 (CoQ10) nephropathy is a well-known cause of hereditary steroid-resistant nephrotic syndrome, primarily impacting podocytes. This study aimed to elucidate variations in individual cell-level gene expression in CoQ10 nephropathy using single-cell transcriptomics.

Methods: We conducted single-cell sequencing of a kidney biopsy specimen from a 5-year-old boy diagnosed with a CoQ10 nephropathy caused by a compound heterozygous COQ2 mutation complicated with immune complex-mediated glomerulonephritis.

Simultaneous Epigenetic and Gene Expression Profiling at Single Cell Resolution Uncovers Stem-Like Treg Subsets Induced With Oligonucleotide Expansion in Humans.

Tregs play a central role in maintaining immune tolerance. Recent progress in the clinical application of Tregs underscores their potential for cell therapy. Nevertheless, a notable hurdle remains in producing functional Tregs .

Genomic profiling of intimal sarcoma reveals molecular subtypes with distinct tumor microenvironments and therapeutic implications.

Background: Intimal sarcoma is a rare and aggressive soft-tissue sarcoma with limited treatment options. We explored genomic profiles of intimal sarcoma to uncover therapeutic implications.

Materials And Methods: We analyzed tumor tissues from patients with intimal sarcoma who visited the Seoul National University Hospital (SNUH) using whole-exome, whole-transcriptome, and clinical next-generation sequencing (NGS), integrated with intimal sarcoma NGS data from two public cohorts.

Real-time continuous glucose monitoring improves postoperative glucose control in people with type 2 diabetes mellitus undergoing coronary artery bypass grafting: A randomized clinical trial.

Background: Effective glycaemic control following cardiac surgery improves clinical outcomes, and continuous glucose monitoring (CGM) might be a valuable tool in achieving this objective. We investigated the effect of real-time CGM and telemonitoring on postoperative glycaemic control in people with type 2 diabetes (T2D) after coronary artery bypass grafting (CABG).

Methods: In this randomized clinical trial (RCT), adults with T2D undergoing CABG were assigned to either a test group utilizing real-time CGM (Dexcom G6) and telemetry for glycaemic control, or a control group with blinded CGM measures, relying on point-of-care measures.

Somatic copy number deletion of chromosome 22q in papillary thyroid carcinoma.

Deletion of the long q arm of chromosome 22 (22qDEL) is the most frequently identified recurrent somatic copy number alteration (SCNA) observed in papillary thyroid carcinoma (PTC). Since its role in PTC is not fully understood, we conducted a pooled analysis of genomic characteristics and clinical correlates in 1094 primary tumors from four published PTC genomic studies. The majority of PTC with 22qDEL exhibited arm-level loss of heterozygosity (86%); nearly all PTC with 22qDEL had losses in 22q12 and 13, which together constitute 70% of the q arm.

Inhibition of nitric oxide synthase transforms carotid occlusion-mediated benign oligemia into large cerebral infarction.

It remains unclear why unilateral proximal carotid artery occlusion (UCAO) causes benign oligemia in mice, yet leads to various outcomes (asymptomatic-to-death) in humans. We hypothesized that inhibition of nitric oxide synthase (NOS) both transforms UCAO-mediated oligemia into full infarction and expands pre-existing infarction. Using 900 mice, we i) investigated stroke-related effects of UCAO with/without intraperitoneal administration of the NOS inhibitor (NOSi) N-nitro-L-arginine methyl ester (L-NAME, 400 mg/kg); ii) examined the rescue effect of the NO-donor, molsidomine (200 mg/kg at 30 minutes); and iii) tested the impact of antiplatelet medications.

Metabolic Aging as an Increased Risk for Chronic Obstructive Pulmonary Disease.

Background/objectives: Both aging and chronic obstructive pulmonary disease (COPD) are strongly associated with changes in the metabolome; however, it is unknown whether there are common aging/COPD metabolomic signatures and if accelerated aging is associated with COPD.

Methods: Plasma from 5704 subjects from the Genetic Epidemiology of COPD study (COPDGene) and 2449 subjects from Subpopulations and intermediate outcome measures in COPD study (SPIROMICS) were profiled using the Metabolon global metabolomics platform (1013 annotated metabolites). Post-bronchodilator spirometry measures of airflow obstruction (forced expiratory volume at one second (FEV)/forced vital capacity (FVC) < 0.

Improved enzyme functional annotation prediction using contrastive learning with structural inference.

Recent years have witnessed the remarkable progress of deep learning within the realm of scientific disciplines, yielding a wealth of promising outcomes. A prominent challenge within this domain has been the task of predicting enzyme function, a complex problem that has seen the development of numerous computational methods, particularly those rooted in deep learning techniques. However, the majority of these methods have primarily focused on either amino acid sequence data or protein structure data, neglecting the potential synergy of combining both modalities.

Temporal Expression Analysis to Unravel Gene Regulatory Dynamics by microRNAs.

MicroRNAs (miRNAs) are a class of small non-coding RNAs (sncRNAs) of length 21-25 nucleotides. These sncRNAs hybridize to repress their target genes and inhibit protein translation, thereby controlling regulatory functions in the cell. Integration of time-series matched small and RNA-seq data enables investigation of dynamic gene regulation through miRNAs during development or in response to a stimulus, such as stress.

Adherence to the Cancer Prevention Recommendations from World Cancer Research Fund/American Institute for Cancer Research After Cancer Diagnosis on Mortality in South Korea.

Background/objectives: The World Cancer Research Fund/American Institute for Cancer Research recommends following the recommendations for cancer prevention even after cancer diagnosis. To provide evidence on the potential benefits of adherence on improved survival, we investigated the effects of post-diagnostic adherence to the recommendations regarding diet, physical activity, and body weight on all-cause mortality among Korean cancer survivors.

Methods: Among the total number of cancer survivors ( = 173,195) recruited from 2004 to 2013 for the Health Examinees study, 5485 were selected for the analyses and classified by tertiles according to the adherence score.

Development of a prime editor with improved editing efficiency in Arabidopsis.

Prime editing is widely used in many organisms to introduce site-specific sequence modifications, such as base substitutions, insertions, and deletions, in genomic DNA without generating double-strand breaks. Despite their wide-ranging applications, prime editors (PEs) have low editing efficiency, especially in dicot plants, and are therefore barely used for genome engineering in these plant species. Here, based on the previous approaches used to improve prime editing efficiency, we generated multiple different combinations of PE components and prime editing guide RNAs (pegRNAs) and examined their prime editing efficiency in Arabidopsis thaliana protoplasts as the dicot model system.

Menopausal hormone therapy: assessing associations with breast and colorectal cancers by familial risk.

Menopausal users of hormone replacement therapy (HRT) are at increased breast cancer risk and decreased colorectal cancer (CRC) risk compared with individuals who have never used HRT, but these opposing associations may differ by familial risk of breast cancer and CRC. We harmonized data from 3 cohorts and generated separate breast cancer and CRC familial risk scores based on cancer family history. We defined moderate or strong family history as a risk score of 0.

Natural language processing and expert follow-up establishes tachycardia association with CDKL5 deficiency disorder.

Purpose: CDKL5 deficiency disorder (CDD) is a developmental and epileptic encephalopathy with multisystemic comorbidities. Cardiovascular involvement in CDD was shown in animal models but is yet poorly described in CDD cohorts.

Methods: We identified 38 individuals with genetically confirmed CDD through the Cleveland Clinic CDD specialty clinic and matched 190 individuals with non-genetic epilepsy to them as a comparison group.

Remote monitoring of social attention in neurogenetic syndromes and idiopathic neurodevelopmental disability.

Social attention is a key aspect of neurodevelopment and is significantly altered in neurodevelopmental genetic syndromes and many individuals with idiopathic autism spectrum disorder (ASD). The primary aim of the present study was to examine the psychometric properties of webcam-collected social attention measurements, including four new specific aspects of social attention, in three genetic syndromes (PTEN Hamartoma Tumor Syndrome-PHTS; Malan Syndrome-NFIX; and SYNGAP1-related disorder-SYNGAP1), a mixed group of other neurodevelopmental genetic syndromes (Other NDGS), and individuals with a range of idiopathic neurodevelopmental disorder (NDD). The secondary aim was to evaluate the construct validity of these social attention measurements, including evaluating known-groups validity across study groups and concurrent validity for separating ASD and non-ASD cases.

Analysis of 1386 epileptogenic brain lesions reveals association with DYRK1A and EGFR.

Lesional focal epilepsy (LFE) is a common and severe seizure disorder caused by epileptogenic lesions, including malformations of cortical development (MCD) and low-grade epilepsy-associated tumors (LEAT). Understanding the genetic etiology of these lesions can inform medical and surgical treatment. We conducted a somatic variant enrichment mega-analysis in brain tissue from 1386 individuals who underwent epilepsy surgery, including 599 previously unpublished individuals with ultra-deep ( > 1600x) targeted panel sequencing.

The incidence of pancreatic cancer in women with a BRCA1 or BRCA2 mutation.

Background: The lifetime risk of pancreatic cancer in women with a germline mutation in BRCA1 and BRCA2 is not well established. In an international prospective cohort of female carriers of BRCA1 and BRCA2 mutations, the cumulative incidence of pancreatic cancer from age 40 until 80 years was estimated.

Methods: A total of 8295 women with a BRCA1 or BRCA2 mutation were followed for new cases of pancreatic cancer.

Impaired chaperone-mediated autophagy leads to abnormal SORT1 (sortilin 1) turnover and CES1-dependent triglyceride hydrolysis.

SORT1 (sortilin 1), a member of the the Vps10 (vacuolar protein sorting 10) family, is involved in hepatic lipid metabolism by regulating very low-density lipoprotein (VLDL) secretion and facilitating the lysosomal degradation of CES1 (carboxylesterase 1), crucial for triglyceride (TG) breakdown in the liver. This study explores whether SORT1 is targeted for degradation by chaperone-mediated autophagy (CMA), a selective protein degradation pathway that directs proteins containing KFERQ-like motifs to lysosomes via LAMP2A (lysosomal-associated membrane protein 2A). Silencing LAMP2A or HSPA8/Hsc70 with siRNA increased cytosolic SORT1 protein levels.